Our previous work has demonstrated that aged monkeys show cognitive loss and accumulation of amyloid and senile plaques in the cerebral cortex similar to changes observed in normal human aging. However monkeys do not show neurofibrillary tangles and there is no major loss of cortical projection neurons in areas so far examined (primary visual and motor cortex, the subiculum of the hippocampal formation). There is cell loss in subcortical sites, including the cholinergic nucleus basalis, and, based upon other studies, there is likely to be cell loss in other subcortical nuclei that provide neurochemically specific afferent input to the cerebral cortex. In addition, we have observed degeneration in intracortical and subcortical white matter and in cortical neuropil that may reflect loss of synaptic input, while other data suggest changes in levels of neurotransmitters and their processing enzymes as well as related receptors. Finally the amyloid proteins in monkey brain are identical to those in human brain. It is not known whether they are the result of direct age-related pathogenic factors or a result of changes in free radical metabolism. The similarity of these behavioral and neurobiological changes with those observed in humans form a basis for our proposed investigation of age-related changes in rhesus monkeys. The overall hypothesis of this project is that cortical pathology underlines the cognitive decline seen in aging monkeys to man. To investigate this hypothesis we propose the following specific aims. We will behaviorally test monkeys that range in age from young adults (5 yrs) to the very elderly (25+ yrs) to assess memory and executive function, and since it is likely that these two cognitive domains are localized primarily in frontal lobe association cortex and the temporal lobe system, respectively, we will examine these areas in detain in a number of ways. We will look for changes in the neuronal population, and especially in the inhibitory neuronal types, and also for loss of synapses, and alteration in glial cells and changes in neurotransmitter levels, metabolism and receptors and the maturation states and distribution of plaques. We will also correlate the changes in neurochemically specific nuclei with cognitive changes of individual monkeys and their cortical pathology since these nuclei provide inputs to the cerebral cortex. To identify pathogenic factors we also assess free radical metabolism and its relationship to alterations in mechanisms of amyloid accumulation. These data will allow us to identify the time of onset and the sequence of structural and metabolic alterations that underlie age-related cognitive decline. We expect these data to provide the basis for a suitable primate model of normal human aging that can eventually be used for evaluation of potential therapeutic intervention.